Splicing potentiation by growth factor signals via estrogen receptor phosphorylation

doi:10.1073/pnas.0503197102

Splicing potentiation by growth factor signals via estrogen receptor phosphorylation

^*Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan; ^†Division of Oral Infectious Diseases and Immunology, Faculty of Dental Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; ^§Department of Biology, Faculty of Science, Kobe University, Nada-ku, Kobe 657-8501, Japan; ^¶Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; and ^‡Exploratory Research for Advanced Technology, Japan Science and Technology, Kawaguchi, Saitama 332-0012, Japan

Contributed by Bert W. O'Malley, April 19, 2005

Abstract

Mitogen-activated protein kinase-mediated growth factor signals are known to augment the ligand-induced transactivation function of nuclear estrogen receptor α (ERα) through phosphorylation of Ser-118 within the ERα N-terminal transactivation (activation function-1) domain. We identified the spliceosome component splicing factor (SF)3a p120 as a coactivator specific for human ERα (hERα) activation function-1 that physically associated with ERα dependent on the phosphorylation state of Ser-118. SF3a p120 potentiated hERα-mediated RNA splicing, and notably, the potentiation of RNA splicing by SF3a p120 depended on hER Ser-118 phosphorylation. Thus, our findings suggest a mechanism by which growth factor signaling can regulate gene expression through the modulation of RNA splicing efficiency via phosphorylation of sequence-specific activators, after association between such activators and the spliceosome.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: uskato{at}mail.ecc.u-tokyo.ac.jp.
Author contributions: Y. Masuhiro, Y. Mezaki, M.S., and S.K. designed research; Y. Masuhiro, Y. Mezaki, M.S., and T.Y. performed research; K.-i.T. and B.W.O. contributed new reagents/analytic tools; Y. Masuhiro, Y. Mezaki, M.S., K.I., J.Y., S.H., B.W.O., and S.K. analyzed data; and B.W.O. and S.K. wrote the paper.
Abbreviations: ERα, estrogen receptor α; hER, human ER; E2, 17β-estradiol; AF, transactivation function; TAM, 4-hydroxy-tamoxifen; SF, splicing factor; snRNP, small nuclear ribonucleoprotein particle; MAPK, mitogen-activated protein kinase; siRNA, short interfering RNA.